Abstracts / Osteoarthritis and Cartilage 25 (2017) S1eS7
Results: We found that proliferative chondrocytes continued proliferation and did not undergo hypertrophy in Sik3 KO mouse embryos. Cartilage volume was larger in Sik3 KO mouse embryos. The activated form of SIK3 was highly expressed in degenerated cartilage from patients with osteoarthritis, but not so in normal cartilage. These results suggest that increased SIK3 activity is associated with osteoarthritis. In order to investigate how Sik3 affects the homeostasis of articular cartilage, we generated cartilage-speciﬁc Sik3 cKO mice in a tamoxifendependent manner. Tamoxifen administration abraded the Sik3 gene and increased the thickness of articular cartilage in Sik3 cKO mice. Sik3 cKO mice showed resistance to the development of DMM-induced osteoarthritis and decreased expression of type X collagen in the noncalciﬁed zone of articular cartilage. These results suggest that Sik3 can be a target for drug development against osteoarthritis. We found the chemical compound pterosin B speciﬁcally inhibits Sik3 activity. Administration of pterosin B alleviated the development of osteoarthritis in DMM mice. Conclusions: Abrasion of Sik3 delayed chondrocyte hypertrophy and increased cartilage volume in embryonic epiphyseal cartilage and articular cartilage after birth in mice. Sik3 deletion conferred resistance to the development of osteoarthritis in mice, suggesting that Sik3 can be a target for treatment. Pterosin B, an inhibitor of Sik3, showed promise as a lead molecule for drug development. I-19 METABOLIC OA; DOES IT EXIST? D. Felson. Boston Univ., Boston, MA Purpose: There is strong evidence that local inﬂammation plays an important role in causing pain in osteoarthritis (OA) and in contributing to worsening structural deterioration of the affected joint. The metabolic syndrome, which increases the risk of heart disease, may inﬂuence OA by magnifying articular inﬂammation or may increase OA risk through other means. The metabolic syndrome consists of a combination of centralized obesity, elevated triglycerides, reduced HDL cholesterol, hypertension and elevated fasting blood sugar, all of which occur more often in obese persons. The purpose of this talk is to review and critically evaluate evidence on the association of metabolic syndrome and OA. Methods: Narrative review Results: A large number of epidemiologic studies have examined the relationship between metabolic syndrome and the occurrence of OA, especially in the knees. Findings from these studies are challenging to interpret. In general, when the studies have adjusted for obesity, a major risk factor for knee OA that confers increased mechanical load on knees, ﬁndings have not shown a consistent association of metabolic syndrome with knee OA. The association of obesity with an increased risk of hand OA has suggested that there is something about systemic adipose tissue accumulation that increases OA risk which might be related to metabolic syndrome. Studies examining the relationship of hand OA with metabolic syndrome have been more positive although not uniformly so. These will be reviewed. A high prevalence of hand OA has been reported in HIV-positive men with metabolic syndrome and this is strong evidence in favor of a relationship between metabolic syndrome and hand OA. A related question is whether any elements of the metabolic syndrome are particularly associated with the risk of OA rather than the metabolic syndrome itself. Initial studies suggested that central obesity may be uniquely related, with visceral fat being a major source of inﬂammatory adipokines. However the analytic approach to examining central obesity is challenging because central obesity and BMI are collinear and straightforward adjustment for BMI is probably not adequate to evaluate the effect of central obesity in causing OA. Several studies have suggested that hypertension is uniquely related to OA risk, and there is conﬂicting evidence regarding the relation of OA to diabetes. Conclusions: The evidence so far does not identify a clearcut association of metabolic syndrome with OA but is suggestive, especially for hand OA. Longitudinal studies are needed including those that focus on speciﬁc elements of metabolic syndrome and that explore biologically why elements of this syndrome might be related to OA risk.
I-20 CLINICAL TESTING IN VETERINARY OA P.D. Hanson. Ctr.xion Therapeutics, Baltimore, MD Premise: The conduct of clinical studies in dogs with naturally occurring osteoarthritis (OA) greatly augments work in animals with induced models. Background: The research and development of new analgesics to manage pain associated with OA in humans and animals typically involves use of induced OA or induced pain models in animals. These models may include use of Freund’s adjuvant, carrageenan, monoiodoacetate, urate crystals, surgical destabilization procedures or other methods in mice, rats, rabbits, guinea pigs, dogs, sheep, horses, and other species. These models may provide an efﬁcacy signal but they also have limitations that vary by model and animal species used. Osteoarthritis occurs in 20% of adult pet dogs, generally, and 80% of dogs greater than 8 years of age. The pathophysiology of OA in dogs is similar to that in humans. Appropriately conducted clinical studies in pet dogs with naturally occurring OA offer greater relevance than induced models to the clinical condition in humans and dogs. This session will discuss clinical assessment of OA in pet dogs, including veterinarian examination, owner scales (eg, Client Speciﬁc Outcomes Measures [CSOM], Canine Brief Pain Inventory [CBPI], Liverpool Osteoarthritis in Dogs [LOAD], Glasgow Composite Measures Pain Scale and Short Form [GCMPS-SF], etc), and objective measures such as ground reaction forces and kinematics. Challenges, such as the caregiver placebo effect, also will be addressed. Regulatory requirements for the conduct of clinical trials in pet dogs will be discussed. Conclusion: Studies in dogs with naturally occurring OA can de-risk human development programs while providing parallel development of new therapeutics to manage OA pain in dogs. I-21 MRI IN OA RESEARCH AND THE CLINIC E. Oei. Erasmus MC, Univ. Med. Ctr., Rotterdam, Netherlands In this lecture current and emerging MRI methods for osteoarthritis (OA) will be reviewed, focusing on the knee joint. A distinction will be made between existing and clinically practical MRI techniques versus novel MRI methods that are still being used mostly as research tools. The recent insights regarding the “multi-tissue” involvement of OA will be highlighted along with the implications for MR imaging. Semiquantitative MRI scoring methods to systematically assess OA features in a variety of joint tissues are discussed, emphasizing the MRI osteoarthritis knee score (MOAKS). These scoring systems are mainly utilized for research purposes, but also provide a helpful template for clinical radiologists that can be applied on routine MRI of the knee. Among the tissue changes discussed are cartilage lesions, bone marrow lesions, synovitis, meniscal lesions, and miscellaneous soft tissue abnormalities that are believed to play a role in OA. Although most current guidelines do not recommend the use of MRI as a routine clinical examination for OA, awareness of relevant OA features may improve reporting of clinical MRI scans especially with the increasing number of MRI examinations being performed, also in older age groups. An overview of novel advanced MRI techniques for osteoarthritis is given, including quantitative techniques to assess tissue composition (delayed gadolinium-enhanced MRI of cartilage, T2- and T1rho mapping, GagCEST and sodium MRI), ultrashort echo time (UTE), PET-MRI and emerging methods to assess synovitis. Selected reported applications of these techniques in OA research will be presented. While these techniques hold promise because of their quantitative nature and improved sensitivity compared to existing methods, many of these will require more validation and technical improvements before they can be applied routinely OA research and the clinic. Take home points: - Osteoarthritis is currently considered a multi-tissue” or “whole organ” disease which affects many tissues in and around the joint. - Hence, MRI provides a more accurate and sensitive assessment of the processes involved in osteoarthritis than radiography, although conventional MRI methods are still looking at relatively advanced stages of osteoarthritis.